Synthetic methods for preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-n-[(1s)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-n-prop-2-ynyl-1,3-thiazol-2-amine

Abstract

The present disclosure relates to the fields of chemistry and medicine, more particularly to processes for making 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thi-azol-2-amine (Compound 1), pharmaceutically acceptable salts, and crystalline forms thereof, for the treatment of congenital adrenal hyperplasia (CAH).

1 . A compound that is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein the enantiomeric excess (e.e. %) of the compound is at least 99.3% as determined by chiral HPLC. 
       
     
     
         2 . The compound according to  claim 1 , wherein Compound 1, or a pharmaceutically acceptable salt thereof, is the free base. 
     
     
         3 . The compound according to  claim 1  or  2 , wherein the enantiomeric excess (e.e. %) of Compound 1, or a pharmaceutically acceptable salt thereof, is at least 99.4%. 
     
     
         4 . The compound according to  claim 1  or  2 , wherein the enantiomeric excess (e.e. %) of Compound 1, or a pharmaceutically acceptable salt thereof, is at least 99.5%. 
     
     
         5 . The compound according to  claim 1  or  2 , wherein the enantiomeric excess (e.e. %) of Compound 1, or a pharmaceutically acceptable salt thereof, is at least 99.6%. 
     
     
         6 . The compound according to  claim 1  or  2 , wherein the enantiomeric excess (e.e. %) of Compound 1, or a pharmaceutically acceptable salt thereof, is at least 99.7%. 
     
     
         7 . The compound according to  claim 1  or  2 , wherein the enantiomeric excess (e.e. %) of Compound 1, or a pharmaceutically acceptable salt thereof, is at least 99.8%. 
     
     
         8 . The compound according to  claim 1  or  2 , wherein the enantiomeric excess (e.e. %) of Compound 1, or a pharmaceutically acceptable salt thereof, is at least 99.9%. 
     
     
         9 . The compound according to any one of  claims 1  to  8 , wherein the enantiomeric excess (e.e. %) of Compound 1, or a pharmaceutically acceptable salt thereof, is 100% or less. 
     
     
         10 . The compound according to any one of  claims 1  to  9 , wherein Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline. 
     
     
         11 . The compound according to any one of  claims 1  to  10 , wherein Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline Form I. 
     
     
         12 . A composition comprising a compound that is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) according to any one of  claims 1  to  11 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The composition according to  claim 12 , wherein Compound 1, or a pharmaceutically acceptable salt thereof, is the free base. 
     
     
         14 . The composition according to  claim 12  or  13 , further comprising a compound that is (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The composition according to  claim 14 , wherein Compound IIa, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount ranging from 1.0% to 0.4%. 
     
     
         16 . The composition according to  claim 14 , wherein Compound IIa, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount ranging from 0.9% to 0.4%. 
     
     
         17 . The composition according to  claim 14 , wherein Compound IIa, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount ranging from 0.8% to 0.4%. 
     
     
         18 . The composition according to  claim 14 , wherein Compound IIa, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount ranging from 0.7% to 0.4%. 
     
     
         19 . The composition according to  claim 14 , wherein Compound IIa, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount ranging from 0.6% to 0.4%. 
     
     
         20 . The composition according to any one of  claims 12  to  19 , further comprising a compound that is (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The composition according to  claim 20 , wherein Compound 9A, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount less than 0.5%. 
     
     
         22 . The composition according to  claim 20 , wherein Compound 9A, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount less than 0.3%. 
     
     
         23 . The composition according to  claim 20 , wherein Compound 9A, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount less than 0.1%. 
     
     
         24 . The composition according to  claim 20 , wherein Compound 9A, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount less than 0.05%. 
     
     
         25 . The composition according to any one of  claims 12  to  24 , further comprising a compound that is (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIb), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein the compound is present in the composition in an amount less than 0.1%. 
       
     
     
         26 . The composition according to  claim 25 , wherein Compound IIb, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount less than 0.05%. 
     
     
         27 . The composition according to any one of  claims 12  to  26 , further comprising ethanol. 
     
     
         28 . The composition according to  claim 27 , wherein ethanol is present in the composition in an amount ranging from 300 ppm to 5000 ppm. 
     
     
         29 . The composition according to  claim 27 , wherein ethanol is present in the composition in an amount ranging from 300 ppm to 3000 ppm. 
     
     
         30 . The composition according to  claim 27 , wherein ethanol is present in the composition in an amount ranging from 300 ppm to 2000 ppm. 
     
     
         31 . The composition according to  claim 27 , wherein ethanol is present in the composition in an amount ranging from 300 ppm to 1000 ppm. 
     
     
         32 . The composition according to  claim 27 , wherein ethanol is present in the composition in an amount ranging from 350 ppm to 600 ppm. 
     
     
         33 . The composition according to  claim 27 , wherein ethanol is present in the composition in an amount ranging from 375 ppm to 550 ppm. 
     
     
         34 . The composition according to any one of  claims 12  to  33 , further comprising propargyl bromide, wherein propargyl bromide is present in the composition in an amount less than 10 ppm. 
     
     
         35 . A composition comprising:
 a. 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof, wherein the enantiomeric excess (e.e. %) of the compound is at least 99.3% as determined by chiral HPLC; and   b. at least one compound selected from:   (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), or a pharmaceutically acceptable salt thereof;   (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa), or a pharmaceutically acceptable salt thereof;   (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIb), or a pharmaceutically acceptable salt thereof;   ethanol; and   propargyl bromide.   
     
     
         36 . The composition according to  claim 35 , wherein Compound 1, or a pharmaceutically acceptable salt thereof, is the free base. 
     
     
         37 . A compound that is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) according to any one of  claims 1  to  11 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, prepared by a process comprising: 
         alkylating (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof: 
       
       
         
           
           
               
               
           
         
         with a Compound of Formula (Ii): 
       
       
         
           
           
               
               
           
         
         wherein: LG is a leaving group; 
         in the presence of an alkylating-step solvent, a phase-transfer catalyst, an alkylating-step base, and water to form 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof. 
       
     
     
         38 . The compound according to  claim 37 , wherein Compound 1, or a pharmaceutically acceptable salt thereof, is the free base. 
     
     
         39 . A composition comprising the compound that is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) according to any one of  claims 1  to  11 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, prepared by a process comprising: 
         alkylating (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof: 
       
       
         
           
           
               
               
           
         
         with a Compound of Formula (Ii): 
       
       
         
           
           
               
               
           
         
         wherein: LG is a leaving group; 
         in the presence of an alkylating-step solvent, a phase-transfer catalyst, an alkylating-step base, and water to form 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof. 
       
     
     
         40 . The composition according to  claim 39 , wherein Compound 1, or a pharmaceutically acceptable salt thereof, is the free base. 
     
     
         41 . A pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising Compound 1, according to any one of  claims 1  to  11 ,  37 , and  38 , or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The pharmaceutical product according to  claim 41 , wherein Compound 1, or a pharmaceutically acceptable salt thereof, is the free base. 
     
     
         43 . The pharmaceutical product according to  claim 41  or  42 , wherein the pharmaceutical product is adapted for oral administration. 
     
     
         44 . A pharmaceutical composition comprising Compound 1, according to any one of  claims 1  to  11 ,  37 , and  38  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         45 . A pharmaceutical composition comprising:
 (a) a compound that is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) according to any one of  claims 1  to  11 :   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; and 
         (b) one or more of an oily phase vehicle, an emulsifying agent, a nonionic surfactant, and a solubilizing agent. 
       
     
     
         46 . A pharmaceutical composition in oral solution dosage form comprising:
 (a) a compound that is 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) according to any one of  claims 1  to  11 :   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof;
 (b) one or more of a sweetener, an anti-oxidant, and a flavor; and 
 (c) a liquid vehicle, wherein the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate/dicaprate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol. 
 
       
     
     
         47 . The pharmaceutical composition according to any one of  claims 44  to  46 , wherein Compound 1, or a pharmaceutically acceptable salt thereof, is the free base. 
     
     
         48 . A compound according to any one of  claims 1  to  11 ,  37 , and  38 , or a pharmaceutically acceptable salt thereof; a composition according to any one of  claims 12  to  36 ,  39 , and  40 ; a pharmaceutical product according to any one of  claims 41  to  43 ; or a pharmaceutical composition according to any one of  claims 44  to  47 ; for use in a method of treatment or prophylaxis of the human or animal body by therapy. 
     
     
         49 . A compound according to any one of  claims 1  to  11 ,  37 , and  38 , or a pharmaceutically acceptable salt thereof; a composition according to any one of  claims 12  to  36 ,  39 , and  40 ; a pharmaceutical product according to any one of  claims 41  to  43 ; or a pharmaceutical composition according to any one of  claims 44  to  47 ; for use in a method of treatment of a disorder in a subject wherein the subject has abnormal levels of CRF 1 . 
     
     
         50 . A compound according to any one of  claims 1  to  11 ,  37 , and  38 , or a pharmaceutically acceptable salt thereof; a composition according to any one of  claims 12  to  36 ,  39 , and  40 ; a pharmaceutical product according to any one of  claims 41  to  43 ; or a pharmaceutical composition according to any one of  claims 44  to  47 ; for use in a method of treatment of a Corticotropin Releasing Factor 1 (CRF 1 ) disorder. 
     
     
         51 . A compound according to any one of  claims 1  to  11 ,  37 , and  38 , or a pharmaceutically acceptable salt thereof; a composition according to any one of  claims 12  to  36 ,  39 , and  40 ; a pharmaceutical product according to any one of  claims 41  to  43 ; or a pharmaceutical composition according to any one of  claims 44  to  47 ; for use in a method of treating congenital adrenal hyperplasia (CAH). 
     
     
         52 . The compound, or a pharmaceutically acceptable salt thereof; the composition; the pharmaceutical product; or the pharmaceutical composition for use according to  claim 51 ; wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia. 
     
     
         53 . The compound, or a pharmaceutically acceptable salt thereof; the composition; the pharmaceutical product; or the pharmaceutical composition for use according to  claim 51  or  52 ; wherein the method of treating congenital adrenal hyperplasia comprises administering a glucocorticoid. 
     
     
         54 . The use of a compound according to any one of  claims 1  to  11 ,  37 , and  38 , or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of a subject wherein the subject has abnormal levels of CRF 1 . 
     
     
         55 . The use of a compound according to any one of  claims 1  to  11 ,  37 , and  38  or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of a Corticotropin Releasing Factor 1 (CRF 1 ) disorder. 
     
     
         56 . The use of a compound according to any one of  claims 1  to  11 ,  37 , and  38  or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of congenital adrenal hyperplasia (CAH). 
     
     
         57 . The use according to  claim 56 ; wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia. 
     
     
         58 . The use according to  claim 56  or  57 ; wherein the treatment of congenital adrenal hyperplasia comprises administering a glucocorticoid. 
     
     
         59 . A method of treating a disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of  claims 1  to  11 ,  37 , and  38 , or a pharmaceutically acceptable salt thereof; a composition according to any one of  claims 12  to  36 ,  39 , and  40 ; a pharmaceutical product according to any one of  claims 41  to  43 ; or a pharmaceutical composition according to any one of  claims 44  to  47 ; wherein the subject has abnormal levels of CRF 1 . 
     
     
         60 . A method of treating a Corticotropin Releasing Factor 1 (CRF 1 ) disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of  claims 1  to  11 ,  37 , and  38 , or a pharmaceutically acceptable salt thereof; a composition according to any one of  claims 12  to  36 ,  39 , and  40 ; a pharmaceutical product according to any one of  claims 41  to  43 ; or a pharmaceutical composition according to any one of  claims 44  to  47 . 
     
     
         61 . A method of treating congenital adrenal hyperplasia (CAH), in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of  claims 1  to  11 ,  37 , and  38 , or a pharmaceutically acceptable salt thereof; a composition according to any one of  claims 12  to  36 ,  39 , and  40 ; a pharmaceutical product according to any one of  claims 41  to  43 ; or a pharmaceutical composition according to any one of  claims 44  to  47 . 
     
     
         62 . The method according to  claim 61 ; wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia. 
     
     
         63 . The method according to  claim 61  or  62 ; wherein the method further comprises administering to the subject a glucocorticoid. 
     
     
         64 . A method for preparing a pharmaceutical composition comprising the step of admixing a compound according to any one of  claims 1  to  11 ,  37 , and  38 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.